694 WOUND HEALING 8 



diameter and 640 A periodicity. Each fibril is surrounded by interfibrillary 

 substance which probably contains either collagen molecules or components 

 necessary for fibrillar enlargement. The fibrogenic cells also contain numerous 

 cytoplasmic granules rich in mucopolysaccharides, alkaline phosphatase, and a 

 protein component (Jackson, 1955). These granules appear to be concerned with 

 synthesis of intercellular material. Probably the cells secrete some substance, which 

 then reacts with interstitial fluid to form intercellular material. The presence of 

 fibrils within the cytoplasm of fibroblasts may be due either to absorption of 

 interstitial fluid or extracellular fibrils. 



The collagen of human skin has a cross-striated appearance with a periodicity 

 of 620-660 A (Gross and Schmitt, 1948). The basic unit is thought to be 210 A, 

 three of which combine to form the regular period. Porter and Vanamee (1949) 

 have found that unit fibers fuse to form larger strands, these small units are prob- 

 ably formed by a lateral association of several protofibrils and progressive deposi- 

 tion of molecular collagen on their surface, a process which can be reversed in 

 vitro (Vanamee and Porter, 1951). Fibers treated with 0.0 1 % acetic acid swell and 

 dissociate into submicroscopic filaments, these in turn can be reconstituted by the 

 addition of neutral salts or elevating the pH, both of which directly influence the 

 architecture of the resulting fiber. A similar mechanism may occur in vivo : Hass 

 and McDonald (1940) have already shown that collagen production in cultures of 

 fibroblasts is regulated by pH. An acid environment (pH 6.6) not only inhibits its 

 production but also causes dissolution of previously formed fibers. 



At present the majority of investigators believe that fibroblasts secrete a soluble 

 protein procollagenous material (Tustanovsky, 1947; Orekhovich et al., 1948), 

 which in turn combines with a carbohydrate fraction of the ground substance to 

 form insoluble collagen. Highberger et al. (1951) have shown that mucoprotein 

 when placed with an extracted collagen solution in vitro will precipitate collagen 

 fibers of normal periodicity, when an excess is added the so-called pro-collagenous 

 fibers of 2000-3000 A periodicity are formed. Various other substances, such as 

 heparin, serum glycoproteins and plant gums, also yield a collagen precipitate 

 indicating that this in vitro reaction is not specific (Gross et al., 1952; Jackson and 

 Randall, 1953). If the normal mucopolysaccharide content of fibroblast cultures is 

 hydrolized with testicular hyaluronidase collagen formation is inhibited (Mancini 

 and De Lustig, 1950). 



Mucopolysaccharides may also exert an indirect influence on collagen produc- 

 tion. The dialized water-extracted material of granulation tissue, which is a rich 

 source, inhibits the growth of fibroblasts in vitro (Balazs and Holmgren, 1949). This 

 inhibition is especially pronounced during the period when the polysaccharide 

 content of granulation tissue is high, i.e. the sixth to ninth day (Balazs and Hom- 

 gren, 1950). Under normal circumstances cell differentiation is inversely propor- 

 tional to cell growth; perhaps mucopolysaccharides contribute to the role of 

 fibroblasts in forming collagen, by inhibiting their excessive growth. 



The source of mucoprotein in the wound area is still an open question. Some 

 workers (Staemmler, 1921; Sylven, 1941; Asboe-Hansen, 1953, 1955) feel that 

 it is secreted by the mast cells. Sylven (1941) based his conclusion on the obser- 

 vation that the number of mast cells as well as their content of granules is de- 



